Lee, R. F. | bioRxiv Science

bioRxiv2025

Planar cell polarity aligns epithelial migration to coordinate tissue architecture and functional zonation

Epithelial tissues must coordinate collective migration with functional specialization to maintain organ integrity, but the mechanisms linking these processes remain unknown. Here, we define the planar cell polarity (PCP) pathway as a master coordinator that translates molecular asymmetry into tissue-scale organization during postnatal intestinal development. We show that PCP drives the developmental transition from random to linear epithelial migration by aligning actin-based basal protrusions and polarizing basement membrane integrins. This creates coherent cellular streams that form characteristic villus ribbons. Strikingly, we discover that disrupting this migration coherence directly perturbs functional zonation, as loss of PCP causes disordered migration that expands specialized metabolic domains beyond their spatial boundaries. These findings reveal a previously unrecognized principle of epithelial organization: directional collective migration actively maintains functional compartmentalization, establishing migration pattern as a fundamental determinant of how tissues preserve specialized function during continuous turnover.

developmental biology↗

bioRxiv2019

Persistence of a novel regeneration-associated transitional cell state in pulmonary fibrosis

Stem cell senescence is often seen as an age associated pathological state in which cells acquire an abnormal and irreversible state. Here, we show that alveolar stem cell differentiation during lung regeneration involves a unique previously uncharacterized transitional state that exhibits cardinal features normally associated with cell senescence. Specifically, using organoid cultures, multiple in vivo injury models coupled with single cell transcriptomics and lineage tracing analysis, we find that alveolar stem cell differentiation involves a novel, pre-alveolar type-1 transitional state (PATS) en route to their terminal maturation. PATS can be distinguished based on their unique transcriptional signatures, including enrichment for TP53, TGF{beta}, and DNA damage repair signaling, and cellular senescence in both in vivo and ex vivo regenerating tissues. Significantly, PATS undergo extensive cell stretching, which makes them vulnerable to DNA damage, a feature commonly associated with most degenerative lung diseases. Importantly, we find enrichment of PATS-like state in human fibrotic lung tissues, suggesting that persistence of such transitional states underlies the pathogenesis of pulmonary fibrosis. Our study thus redefines senescence as a state that can occur as part of a normal tissue maintenance program, and can be derailed in human disease, notably fibrosis.

cell biology↗